The human T-cell leukemia virus, HTLV-I, has been established as the etiological agent for adult T-cell leukemia. The 3' long open reading frame of the human T-cell leukemia virus type-I (HTLV-I) encodes a 40 kD protein (tax1). This protein positively regulates transcription directed by the HTLV-I long terminal repeat (LTR) in a phenomenon known as trans-activation. We have been unable to attribute any sequence-specific DNA binding properties to tax1, suggesting that the protein activates the HTLV-L promoter in an indirect fashion using cellular transcription factors. Our objective is to understand the biochemical mechanism of trans-activation by the tax1 protein and the involvement of cellular transcription factors in this process. Important findings include: 1) tax1 appears to trans-activate responsive LTR elements through the induction of a 180 kD cellular protein; 2) mutational analyses correlate the trans-activation of the HTLV-I LTR by tax1 with the presence of a cAMP responsive octonucleotide; 3) two signal transduction agents, cAMP and TPA, are both potent activators of the HTLV-I LTR. Relevant to the last observation, we have defined both the cAMP-responsive and the TPA-responsive sequence elements with the HTLV-I LTR; 4) tax1 interacts indirectly, most likely through protein-protein interaction, to tax1 responsive sequences in the HTLV-I LTR; and 5) tax1 binding to the HTLV-I LTR is mediated by a 36 kD cellular protein.